Highlights from Recent Cancer Literature
Journal: Cancer Research (2017)

Genomic studies have unveiled frequently altered pathways and mutated genes in glioblastoma but have failed to translate into effective therapeutic interventions in vivo. Miller and colleagues compared parallel glioblastoma RNAi screens in vitro and in vivo on orthotopic patient-derived xenografts. Their data revealed an alarmingly small overlap among the genes vital for growth under these two conditions. In vitro, growth and survival was dependent on genes involved mainly in regulation of cell metabolism and production of macromolecules. In contrast, silencing of transcription pause-release and elongation factors delayed tumor progression and prolonged survival in mouse models. These factors, including JMJD6, allowed cancer cells to adapt transcriptionally to their microenvironment and survive. These exciting data raise serious concerns about using cell line studies to identify clinically relevant pathways in cancer as tumor-stroma cross-talk and the microenvironment play such decisive roles.Miller TE, Liau BB, Wallace LC, Morton AR, Xie Q, Dixit D, et al. Transcriptional elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 2017;547:355–9.Genetic and epigenetic defects in hematopoietic cells are known to drive myelodysplastic syndrome (MDS). However, there is growing evidence that defects in stromal cells may contribute to disease progression too. Bhagat and colleagues analyzed bone marrow–derived stromal cells from patients with MDS and observed widespread aberrant cytosine hypermethylation outside CpG islands. In patients that received the DNA methyltransferase inhibitor 5-azacytidine, the stroma lacked aberrant methylation and better supported erythroid differentiation. Integrative expression analysis identified aberrant hypermethylation and underexpression of the WNT pathway antagonist FRZB in MDS stroma. These results were confirmed in sorted primary MDS-derived mesenchymal cells. Advanced cases of MDS showed activation of WNT/β-catenin in CD34+ cells, correlating inversely with prognosis. In the NUP98-HOXD13 mouse model of MDS, constitutive β-catenin activation in hematopoietic cells resulted in lethal myeloid disease, further confirming its role in disease progression. Thus, the authors have identified novel epigenetic changes in the bone marrow microenvironment that result in β-catenin activation and MDS disease progression.Bhagat T, Chen S, Bartenstein M, Barlowe TS, von Ahrens D, Choudhary GS, et al. Wnt/ß-catenin activation by epigenetically aberrant stroma drives myelodysplastic syndrome. Cancer Research; Published OnlineFirst July 6, 2017; doi: 10.1158/0008-5472.CAN-17-0282.Molecular targets for prostate cancer, particularly metastatic castrate-resistant prostate cancer (mCRPC), are continually being studied. Audet-Walsh and colleagues explored mTOR as an androgen receptor (AR) cofactor with dominant roles in transcription-mediated metabolic reprogramming of prostate cancer cell metabolism and as an alternative new therapeutic target in mCRPC. They showed that AR and mTOR formed a complex and that AR drove mTOR DNA binding to specific androgen-regulated loci. Furthermore, mTOR was required for specific AR-mediated transcriptional programs involving metabolic reprogramming, with functional effects on prostate cancer cell metabolism in vitro. Inhibition of mTOR markedly hindered glucose uptake and aerobic glycolysis, leading to decreased proliferation and migration. High levels of nuclear mTOR were associated with aggressive prostate cancer in patients, and an mTOR gene signature could stratify higher rates of disease recurrence. Thus, therapies developed for cytoplasmic mTOR inhibition might also be coopted for treatment of mCRPC driven metabolically by an AR-nuclear mTOR axis.Audet-Walsh E, Dufour CR, Yee T, Zouanat FZ, Yan M, Kalloghlian G, et al. Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer. Genes &amp; Development; Published in Advance July 19, 2017; doi:10.1101/gad.299958.117.Cancer genome sequencing studies have identified several cancer driver genes that are a result of alterations in protein-coding regions. Potential cancer drivers in noncoding regions, including promoters, however, remain relatively unexplored. Rheinbay and colleagues report a computational method to identify noncoding cancer-associated mutations. Applying their methodology to 360 primary breast tumors, they identified recurrent mutations in the promoters of nine genes. Promoter-proximal mutations in FOXA1, RMRP, and NEAT1 noncoding RNA genes, known to be associated with breast (FOXA1, NEAT1) and epithelial (RMRP) cancers, led to alterations in gene expression and protein binding. Specifically, promoter-proximal mutations of FOXA1, a driver of estrogen receptor–positive breast cancer, led to overexpression through increased binding of the E2F transcription factor. These findings demonstrate possible mechanisms by which genes without coding region mutations can become deregulated in cancer and could identify novel genes associated with oncogenesis.Rheinbay E, Parasuraman P, Grimsby J, Tiao G, Engreitz JM, Kim J, et al. Recurrent and functional regulatory mutations in breast cancer. Nature 2017;547:55–60.Activating mutations in the BRAF oncogene are common in melanoma, lung, colorectal, and thyroid cancers. Treatments that target BRAF or MEK kinases can be effective, but resistance usually develops as the tumors adapt to therapy. Xue and colleagues leveraged 11 patient-derived xenograft (PDX) models from patients previously treated with chemotherapy and/or targeted RAF inhibitors. They observed that ERK inhibition was limited by de novo resistance. Single-cell sequencing in parental-resistant PDX pairs revealed amplification of BRAF in several independent clones. Interestingly, sequential therapy with RAF or MEK inhibitors prior to ERK inhibition resulted in propagation of BRAF-amplified cells compared with triple combinatorial therapy. Tumors that regrew following discontinuation of two-drug regiments had higher BRAF copy number and protein levels compared with three-drug regimens, with less toxicity. Survival was also significantly increased using intermittent combination therapy across 13 PDX models of lung cancer and melanoma. These data provide robust preclinical rationale to quickly move intermittent combinatorial therapy into early phase clinical trials for BRAF-mutated tumors.Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TT, et al. An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer. Nature Medicine; Published online July 17, 2017; doi: 10.1038/nm.4369.Colorectal cancer is the most common gastrointestinal malignancy and a leading cause of cancer mortality. Advances in understanding the biology of colorectal cancer are identifying new therapeutic targets. Using human colorectal cancer cells and tissues, Yokoyama and colleagues demonstrate that bone morphogenetic protein 4 (BMP-4) is universally overexpressed, leading to activation of BMP signaling. The elevated expression of BMP-4 was due to aberrant activation of the Wnt/β-catenin signaling pathway. Inhibition of endogenous BMP signaling using the BMP type I receptor inhibitor LDN-193189 increased phosphatase DUSP5 expression in colorectal cancer cells. The increase in DUSP5 induced apoptosis via dephosphorylation of Erk MAPK. In vivo, LDN-193189 reduced the ability of colorectal cancer cells to form tumors in mice. These studies suggest that inhibition of autocrine BMP-4 signaling might serve as a novel candidate treatment strategy for colorectal cancer.Yokoyama Y, Watanabe T, Tamura Y, Hashizume Y, Miyazono K, Ehata S. Autocrine BMP-4 signaling is a therapeutic target in colorectal cancer. Cancer Res 2017;77:4026–38.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.